Bone defects can be treated by the implantation of an autograft, an allograft, or a xenograft in the healing site. However, these biological implants suffer of many drawbacks, among them, for example, shortage of donor tissue, bacterial and viral contamination, etc. Biocompatible synthetic implants generally present less osteoconductive and osteoinductive effects than biological grafts. But they are usually save and can be manufactured in a reproducible manner.
In dental treatment, for example, the extraction of a tooth leaves an open wound that might be contaminated by bacteria. Moreover, it is a known problem that due to the absence of the tooth, alveolar bone spontaneously undergoes remodeling, leading to its atrophy. Such atrophy may then cause many complications for subsequent reconstruction. In order to prevent this process, it has been suggested in the prior art (U.S. Pat. No. 6,132,214) to implant into the extraction site a biodegradable implant, which is an exact copy of the extracted tooth. Although such implants lead to promising results, the bone in-grow in the alveolar site is relatively low, in particular in the early stage of the healing process. The use of poly(α-hydroxy acids), such as, for example polyglycolide, polylactide, or co-polymers thereof, leads to a massive release of acidic products in the environment of the implant during its degradation. This acidification of the environment may then even provoke tissue necrosis.
While the problems of the prior art have been described with reference to dental problems it will be appreciated by those skilled in the art that implants are also used as treatments for other skeleton parts. If, for example, a part of the skeleton is stricken by a tumor, the area stricken by the tumor may be removed and replaced by an implant. In that case with the implants known from the prior art similar problems as those described with respect to dental treatments may arise.
Other known implant systems and methods include, for example U.S. Pat. No. 5,741,329. In this reference, it is suggested to control the changes of the pH value in the vicinity of biodegradable implants. Thus, during the degradation of the implant the pH value is effectively maintained between 6 and 8 by incorporating a basic salt, preferably calcium carbonate or sodium bicarbonate into a polymeric matrix, preferably poly(lactide-co-glycolide) with a lactide to glycolide molar ratio of 50/50. An amount of about 5% to about 30% of ceramic particles is dispersed in the polymer. The resultant porous implants are only poorly interconnected and have only poor mechanical stability.
In DE-A-31 06 445 a combination of osteoconductive bioceramics with biodegradable polymers is proposed in order to prepare osteoconductive biodegradable implants. Porous tricalcium phosphate ceramics are impregnated with a therapeutically active sub stance, which is disposed in the pores of the ceramics body. For controlling the release of the therapeutically active substance the sintered bioceramic is then coated with a polymer film (e.g. polydextran). In U.S. Pat. No. 4,610,692 it is suggested to impregnate a porous sintered tricalcium phosphate body with therapeutically active substances, such as antibiotics (e.g. gentamicin). and/or disinfecting substances (e.g. polyvinyl pyrrolidone iodine). The release of these substances is controlled by coating the sintered bioceramic porous body with a polymer film (e.g. polymethacrylate, polylactide, polydextran).
From the prior art there are already known open porous implants which are made from an aggregation of granules. In U.S. Pat. No. 5,626,861, a polymer matrix consisting preferably of 50/50 polylactide/polyglycolide copolymer is described, which is reinforced with particulate hydroxyapatite. This combination of materials of materials is supposed to permit to maintain the integrity of the implant as the degradation proceeds. Also the osteoconductive potential is supposedly increased. In the manufacture of the implant particulate hydroxyapatite having an average particle size of about 10-100 μm, and inert leachable particles (e.g. NaCl of a particle size of about 100-250 μm) are suspended in a PLGA solvent solution. The polymer solvent solution is emulsified and cast into any appropriate mold. As the solvent is evaporated from the salt, ceramics and polymer mixture, the dried material retains the shape of the mold. The salt particles within the implant are then leached out by immersion in water. By this method pores having a diameter of about 100-250 μm are left in the implant. The major drawback of this method is the necessity of a complete removal of the organic solvent, which takes time and requires costly analysis before the implant may be applied to the patient in order to treat bone defects.
In U.S. Pat. No. 5,866,155 a method for the manufacture of three-dimensional macroporous polymer matrices for bone graft is suggested. For that purpose calcium phosphate based materials are added to polymer microspheres in order to produce flexible matrices for bone replacement or tissue engineering. In one embodiment a sintered microsphere matrice is prepared. A mixture containing degradable polymer microspheres, calcium phosphate based materials and porogen particles (NaCl) is cast in a mold, compressed and sintered such, that the microspheres of the cast mixture bond to each other after heating over their glass transition temperature. After removal from the mold and cooling, the porogen is leached out in order to produce a matrice for use in bone replacement. In a second embodiment it is described that the microspheres a bonded together by using an organic solvent. After removal of the solvent and leaching out of the porogen material three-dimensional structures are obtained for bone replacement. A still further alternative method consists in the preparation of gel-like polymer microspheres, having sticky surfaces. Calcium-phosphate particles are then added to the sticky microspheres. The mixture is stirred, cast in a mold and dried in order to obtain the desired open porous structure.
Lu et al. in “3D Porous Polymer Bioactive Glass Composite Promotes Collagen Synthesis and Mineralization of Human Osteoblast-like Cells”, Sixth World Biomaterials Congress Transactions, Hawaii, (2000), p: 972 describe a method to prepare 3-D constructs made of Bioglass® 45S5 and poly(lactide-co-glycolide). The method consists of the dissolution of the polymer in a methylene chloride and the addition of Bioglass granules having a size of less than 40 μm, to the solution. The mixture is then poured into a 1% polyvinyl alcohol solution and the spheres are allowed to harden. 3-D constructs are made by heating the microspheres in a mold at 70° C. for 20 hours. The method suffers the disadvantage that it is very difficult to control the degree of deposition of the polymer on the surface of the bioglass granules. An aggregation of the granules is also difficult to avoid. A heat treatment of the granules generally leads to problems, in particular if highly volatile and/or thermolabile biologically active substances, such as, for example, growth factors, are to be added to the granules.
In U.S. Pat. No. 6,203,574 it is suggested to bond ceramic granules with each other using a biodegradable substance. By the suggested method an interconnecting open porous structure is supposed to be obtained. Hydroxyapatite particles of sizes from 100-300 μm are heated to 200° C., while polylactide particles having a particle size smaller than 210 μm are heated to 100° C. The hydroxyapatite particles are then added to the polylactide particles. The mixture is intimately shaken in order to obtain a homogeneous mixture of particles. By this method the polylactide adheres to the surface of the hydroxyapatite particles. Thereafter, a mixture of polylactide particles containing fine hydroxyapatite and polylactide granules with a size of 210-420 μm is added to the coated large hydroxyapatite particles. The resulting mixture is poured into a mold and heated to 195° C. After cooling a molded open porous implant is obtained. However, this method suffers a number of drawback. The particles are bonded together in a heating process, which excludes the incorporation of thermally labile osteoinductive substances such as growth factors or other proteins. Antibiotics can also be altered and even destroyed by the necessary elevated temperatures. Although the polylactide particles are supposed to adhere to the surface of the ceramic particles they can also adhere to each other. Thus, aggregates of polylactide are formed. This can lead to the formation of inhomogeneous implants. The suggested method does not allow the control of the thickness and homogeneity of the coating of the ceramic particles. Thus, the suggested system may not be optimal for a controlled delivery of pharmaceutically active substances. Moreover, the suggested method is incompatible with the desire to use as little polylactide as possible for the production of implants.